Genetic Variant RHOF:p.Ala58Thr (chr12-121793206-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_019034.3(RHOF):c.172G>A(p.Ala58Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,398,566 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

RHOF
NM_019034.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.869

Variant links:

Genes affected

RHOF (HGNC:15703): (ras homolog family member F, filopodia associated) Predicted to enable GTP binding activity; GTPase activity; and protein kinase binding activity. Involved in actin filament organization. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

RHOF links:

SETD1B (HGNC:29187): (SET domain containing 1B, histone lysine methyltransferase) SET1B is a component of a histone methyltransferase complex that produces trimethylated histone H3 at Lys4 (Lee et al., 2007 [PubMed 17355966]).[supplied by OMIM, Mar 2008]

SETD1B links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1878719).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RHOF	NM_019034.3 link	c.172G>A	p.Ala58Thr	missense_variant	Exon 2 of 5	ENST00000267205.7	NP_061907.2	Q9HBH0-1
SETD1B	XM_047428553.1 link	c.-15+383C>T		intron_variant	Intron 1 of 16		XP_047284509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RHOF	ENST00000267205.7 link	c.172G>A	p.Ala58Thr	missense_variant	Exon 2 of 5	1	NM_019034.3	ENSP00000267205.2		Q9HBH0-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000143

AC:

AN:

1398566

Hom.:

Cov.:

AF XY:

0.00000290

AC XY:

AN XY:

689820

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000185

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.172G>A (p.A58T) alteration is located in exon 2 (coding exon 2) of the RHOF gene. This alteration results from a G to A substitution at nucleotide position 172, causing the alanine (A) at amino acid position 58 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

T;.;.

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.34

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.80

T;D;D

M_CAP

Benign

0.059

MetaRNN

Benign

0.19

T;T;T

MetaSVM

Benign

-0.82

MutationAssessor

Benign

-0.11

N;N;.

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.4

N;.;N

REVEL

Benign

0.24

Sift

Benign

0.18

T;.;T

Sift4G

Benign

0.27

T;T;T

Polyphen

0.0

B;B;.

Vest4

0.046

MutPred

0.46

Gain of catalytic residue at S59 (P = 2e-04);Gain of catalytic residue at S59 (P = 2e-04);Gain of catalytic residue at S59 (P = 2e-04);

MVP

0.76

MPC

0.25

ClinPred

0.76

GERP RS

2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.16

gMVP

0.44

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over